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Averbukh LD, Turshudzhyan A, Wu DC, Wu GY. Statin-induced Liver Injury Patterns: A Clinical Review. J Clin Transl Hepatol 2022; 10:543-552. [PMID: 35836753 PMCID: PMC9240239 DOI: 10.14218/jcth.2021.00271] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/09/2021] [Accepted: 11/08/2021] [Indexed: 12/04/2022] Open
Abstract
Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.
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Affiliation(s)
- Leon D. Averbukh
- Department of Medicine, Division of Gastroenterology-Hepatology, Allegheny Health Network, Pittsburgh, PA, USA
- Correspondence to: Leon D. Averbukh, Allegheny Health Network, 320 East North Avenue, 7th Floor, South Tower, Pittsburgh, PA 15212, USA. ORCID: https://orcid.org/0000-0002-7739-7689. Tel: +1-412-359-3846, Fax: +1-412-442-2139, E-mail:
| | - Alla Turshudzhyan
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - David C. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Muñoz AE, Pollarsky FD, Marino M, Cartier M, Vázquez H, Salgado P, Romero G. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol 2021; 27:4639-4652. [PMID: 34366626 PMCID: PMC8326251 DOI: 10.3748/wjg.v27.i28.4639] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/26/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.
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Affiliation(s)
- Alberto E Muñoz
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Florencia D Pollarsky
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mónica Marino
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mariano Cartier
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Horacio Vázquez
- Unidad Clínica, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Investigador Asociado del Gobierno de la Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Pablo Salgado
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Gustavo Romero
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
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Li LZ, Zhao ZM, Zhang L, He J, Zhang TF, Guo JB, Yu L, Zhao J, Yuan XY, Peng SQ. Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway. J Appl Toxicol 2019; 39:1394-1404. [PMID: 31423616 DOI: 10.1002/jat.3825] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/30/2019] [Accepted: 04/30/2019] [Indexed: 12/27/2022]
Abstract
Atorvastatin (ATO) is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin-induced liver injury. This study investigated mechanisms of ATO-induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase-2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration-dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria-dependent apoptosis as indicated by increased Bax/Bcl-2 ratio, cleaved caspase-3, mitochondrial cytochrome c release and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tert-butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO-induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria-dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO-induced liver injury.
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Affiliation(s)
- Li-Zhong Li
- Academy of Military Medical Sciences, Beijing, People's Republic of China.,PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Zeng-Ming Zhao
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Li Zhang
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Jun He
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Ting-Fen Zhang
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Jia-Bin Guo
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Lin Yu
- Academy of Military Medical Sciences, Beijing, People's Republic of China.,PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Jun Zhao
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Xiao-Yan Yuan
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Shuang-Qing Peng
- PLA Center for Disease Control and Prevention, Beijing, People's Republic of China
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Villani R, Navarese EP, Cavallone F, Kubica J, Bellanti F, Facciorusso A, Vendemiale G, Serviddio G. Risk of Statin-Induced Hypertransaminasemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Mayo Clin Proc Innov Qual Outcomes 2019; 3:131-140. [PMID: 31193835 PMCID: PMC6544559 DOI: 10.1016/j.mayocpiqo.2019.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/16/2019] [Accepted: 01/19/2019] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE To assess the effect of statins compared with placebo on the risk of developing hypertransaminasemia. PATIENTS AND METHODS We performed a systematic review of electronic databases and included articles published between January 1, 1965, and April 10, 2017. Randomized clinical trials (RCTs) comparing statins vs placebo were included. Odds ratios (ORs) were pooled in random-effect meta-analyses according to established methods recommended by the Cochrane Collaboration. RESULTS Seventy-three eligible RCTs, comprising 123,051 patients, were identified. Statins associated with a significantly risk of hypertransaminasemia (OR 1.45; 95% confidence interval [CI], 1.24-1.69; P<.001). Atorvastatin showed the highest odds (OR 2.66; 95% CI, 1.74-4.06; P<.001) followed by rosuvastatin (OR 1.35; 95% CI, 1.06-1.70; P=.01) and lovastatin (OR 1.53; 95% CI, 1.03-2.28; P=.04). Pravastatin, fluvastatin, and simvastatin yielded no statistically different odds compared with placebo. CONCLUSIONS A dose-dependent risk of developing hypertransaminasemia occurs in patients taking atorvastatin, rosuvastatin, and lovastatin.
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Eliano Pio Navarese
- Inova Heart and Vascular Institute, Fairfax, Virginia
- Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Francesco Cavallone
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Jacek Kubica
- Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Francesco Bellanti
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Antonio Facciorusso
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Gaetano Serviddio
- C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
- Correspondence: Address to Gaetano Serviddio, MD, C.U.R.E. (Centro per la Ricerca e la Cura delle Epatopatie), Institute of Internal Medicine, Viale Pinto 1, 71122 Foggia, Italy.
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Björnsson ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver Int 2017; 37:173-178. [PMID: 27860156 DOI: 10.1111/liv.13308] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 10/26/2016] [Indexed: 02/13/2023]
Abstract
Statins are generally well tolerated and adverse effects are relatively rare. Clinical trials are underpowered to detect uncommon adverse effects such as idiosyncratic drug-induced liver injury. This review is aimed at covering the current knowledge on the hepatotoxicity associated with statins and other lipid lowering drugs. Both atorvastatin and simvastatin have been associated with more than 50 case reports of liver injury and other statins have been implicated in this type of liver injury as well. Idiosyncratic liver injury due to statins has been reported to occur 1.9%-5.5% of patients in prospective series of drug-induced liver injury. Atorvastatin and simvastatin have been associated with positive rechallenge and some case reports have described liver injury following dose escalation of the implicated statin. Mortality from liver injury and/or liver transplantation has been documented in a few patients with statin induced liver injury although the vast majority of patients with liver injury have recovered after cessation of therapy.
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Affiliation(s)
- Einar S Björnsson
- Faculty of Medicine, The National University Hospital of Iceland, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Skaro AI, Gallon LG, Lyuksemburg V, Jay CL, Zhao L, Ladner DP, VanWagner LB, De Wolf AM, Flaherty JD, Levitsky J, Abecassis MM, Gheorghiade M. The impact of coronary artery disease on outcomes after liver transplantation. J Cardiovasc Med (Hagerstown) 2016; 17:875-885. [DOI: 10.2459/jcm.0000000000000207] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Cannistrà M, Grande R, Ruggiero M, Novello M, Zullo A, Bonaiuto E, Vaccarisi S, Cavallari G, Serra R, Nardo B. Resection of hepatocellular carcinoma in elderly patients and the role of energy balance. Int J Surg 2016; 33 Suppl 1:S119-25. [PMID: 27353847 DOI: 10.1016/j.ijsu.2016.06.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Progressive functional impairment with age has a significant impact on perioperative risk management. Chronic liver diseases induce a strong oxidative stress; in the elderly, in particular, impaired elimination of free radicals leads to insufficient DNA repair. The events associated with a weak response to growth factors after hepatectomy leads to a decline in liver regeneration. Hypercholesterolemia is highly prevalent in the elderly, which may alter the coenzyme Q10 (CoQ) levels and in turn the cellular energy balance. This condition is commonly treated with statins. The aim of this study is to investigate the role of preoperative cellular energy balance in predicting hepatocellular carcinoma (HCC) postresection outcomes. MATERIALS AND METHODS In a 5-year period (2009-2013), elderly patients with hypercholesterolemia, cardiovascular disease, and diabetes mellitus, undergoing HCC resection, were recruited and grouped by age (<75 and ≥ 75 years old). All patients were previously treated with statins. The risk factors associated with hospital morbidity/mortality and prolonged length of stay (LOS) were evaluated. RESULTS Forty-five elderly patients were recruited and grouped according to their treatment: Group 1 (n = 23) was treated with statins alone (control group), whereas Group 2 (n = 22) was treated with statins and a CoQ analogue, 3 weeks from the surgery and at least a month later (experimental group). The majority of our patients were treated with atorvastatin [n = 28 (53.84%)] and the minority with simvastatin [n = 17 (32.69%)], 20 mg/day, for at least 3 years before the surgery. Perioperative mortality was observed in one patient of Group 1 (4.3%). Morbidities were noted in 13 patients of Group 1 (56.5%) and four patients of Group 2 (18.2%). The control group showed delayed functional recovery, muscle weakness, increased infection rate, and pleural effusion due to prolonged bed rest (hospital stay 13 days (7-19) vs. 8.5 days (5-12)), compared with the experimental group. The overall survival at 5 years was similar for both groups (n = 10 patients (43%) in Group 1 vs. n = 10 patients (45%) in Group 2). CONCLUSION In the elderly population, survival is closely linked to postoperative morbidity and mortality. In our study, prolonged LOS was found to be related to delayed bioenergetic recovery. When limited, risk factors such as infections, neutropenia, and red blood cell transfusions could lower LOS and mortality of elderly patients with HCC. Higher age was associated with greater postoperative morbidity and successful hospital stay.
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Affiliation(s)
- Marco Cannistrà
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Raffaele Grande
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Michele Ruggiero
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Matteo Novello
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
| | - Alessandra Zullo
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | | | | | - Giuseppe Cavallari
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Bruno Nardo
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
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Clarke AT, Johnson PCD, Hall GC, Ford I, Mills PR. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort. PLoS One 2016; 11:e0151587. [PMID: 26983033 PMCID: PMC4794178 DOI: 10.1371/journal.pone.0151587] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 03/01/2016] [Indexed: 12/11/2022] Open
Abstract
Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.
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Affiliation(s)
- Alan T. Clarke
- Dept. of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, United Kingdom
- * E-mail:
| | - Paul C. D. Johnson
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | | | - Ian Ford
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom
| | - Peter R. Mills
- Dept. of Gastroenterology, Gartnavel General Hospital, Glasgow, United Kingdom
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Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes. Toxicol In Vitro 2014; 28:1136-43. [DOI: 10.1016/j.tiv.2014.05.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/26/2014] [Accepted: 05/29/2014] [Indexed: 01/01/2023]
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Jose J, Al-Tamimi FAA, Helal MM, Jimmy B, Al Riyami Q. Statin associated hepatic adverse effects: a retrospective review from a regional hospital in sultanate of oman. Oman Med J 2014; 29:351-7. [PMID: 25337312 PMCID: PMC4202230 DOI: 10.5001/omj.2014.93] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 08/03/2014] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE This study aimed at evaluating the prevalence, pattern and predisposing factors for hepatic adverse effects with statins in a regional hospital in Sultanate of Oman. METHODS A retrospective review of the patient files in Department of Medicine during the year 2011 was done to evaluate any hepatic dysfunction possibly related to statins among the patients. For each case of suspected statin induced hepatic effect, additional details on temporal relationship, pattern of presentation, management, final outcome and any contributing factors were obtained. Difference in the occurrence of hepatic effects based on the patient demographics and drug characteristics was additionally evaluated. RESULTS A total of 927 patients meeting the inclusion criteria were included for the study. Mean age of the evaluated patients was 63.1 ± 11.37 and median duration of use of statin in months was 22 (IQR, 43.25). In 40 (4%) of the 927 patients, there was presence of a hepatic effect considered to be statin related and only in 12 (1%) patients a significant transaminase rise (>3 times) was observed. Median duration of use of statin among those patients who developed suspected statin induced hepatic effects and those who did not was 45 (IQR,52) and 21 (IQR, 43) months, respectively and the difference observed was statistically significant. A significant difference in the prevalence of hepatic effects was observed only based on the duration of statin use. CONCLUSION There was an infrequent occurrence of significant hepatic effects associated with statins in the study population. Our results support the latest recommendations including from United States Federal Drug Administration (US FDA) that statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of transaminases does not appear to detect or prevent serious liver injury in association with statins.
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Affiliation(s)
- Jimmy Jose
- Assistant Dean (Research) and Associate Professor, School of Pharmacy, College of Pharmacy and Nursing, University of Nizwa,P.B No 33, PO 616, Birkat Al Mouz, Nizwa, Sultanate of Oman
| | - Faisal Abdullah Ali Al-Tamimi
- Senior Consultant, Physician & Rheumatologist, Department of Medicine, Nizwa Hospital, Ministry of Health, Sultanate of Oman
| | - Manal Mahmoud Helal
- Senior Specialist, Department of Medicine, Nizwa Hospital, Ministry of Health, Sultanate of Oman, and Associate Professor, General Medicine, Cairo University, Egypt
| | - Beena Jimmy
- Lecturer, School of Pharmacy, College of Pharmacy and Nursing, University of Nizwa, Nizwa, Sultanate of Oman
| | - Qasim Al Riyami
- Assistant Dean (Training) School of Pharmacy, College of Pharmacy and Nursing, University of Nizwa, Nizwa, Sultanate of Oman
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11
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Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, Chalasani N, Bonkovsky HL. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014; 60:679-86. [PMID: 24700436 PMCID: PMC4110177 DOI: 10.1002/hep.27157] [Citation(s) in RCA: 173] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/28/2014] [Accepted: 03/30/2014] [Indexed: 12/11/2022]
Abstract
UNLABELLED The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins. Among 1,188 cases of drug-induced liver injury enrolled between 2004 and 2012 in a prospective registry by the U.S. Drug Induced Liver Injury Network, 22 were attributed to a statin. All patients were evaluated in a standard fashion and followed for at least 6 months after onset. The median age was 60 years (range 41-80), and 15 (68%) were female. The latency to onset of liver injury ranged from 34 days to 10 years (median = 155 days). Median peak levels were alanine aminotransferase 892 U/L, alkaline phosphatase 358 U/L, and total bilirubin 6.1 mg/dL. Nine patients presented with cholestatic hepatitis and 12 patients presented with hepatocellular injury, of which six had an autoimmune phenotype. Nine patients were hospitalized, four developed evidence of hepatic failure, and one died. All commonly used statins were implicated. Four patients developed chronic liver injury, of which three had an autoimmune phenotype of liver injury. CONCLUSION Drug-induced liver injury from statins is rare and characterized by variable patterns of injury, a range of latencies to onset, autoimmune features in some cases, and persistent or chronic injury in 18% of patients, most of whom have an autoimmune phenotype.
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Affiliation(s)
- Mark W. Russo
- Carolinas Medical Center, Transplant Center; Charlotte NC
| | - Jay H. Hoofnagle
- the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Jiezhun Gu
- the Duke Clinical Research Institute, Duke University, Durham, NC
| | - Robert J. Fontana
- the University of Michigan School of Medicine, Department of Medicine, Ann Arbor, MI
| | - Huiman Barnhart
- the Duke Clinical Research Institute, Duke University, Durham, NC
| | - David E. Kleiner
- the National Cancer Institute, Laboratory of Pathology, National Institutes of Health, Bethesda, MD
| | - Naga Chalasani
- the Indiana University School of Medicine, Department of Medicine, Indianapolis, IN
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Abstract
Objective: In this case report, we describe the development of an acute autoimmune hepatitis associated with a short course of minocycline prescribed for a skin infection. Due to a drug shortage, minocycline was substituted for doxycycline. Conclusions: It is imperative that practitioners be aware of the different risks that accompany switching between drugs in the tetracycline class, particularly the risk of autoimmune conditions including hepatitis.
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13
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Bergmann OM, Kristjansson G, Jonasson JG, Björnsson ES. Jaundice due to suspected statin hepatotoxicity: a case series. Dig Dis Sci 2012; 57:1959-64. [PMID: 22075853 DOI: 10.1007/s10620-011-1950-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 10/12/2011] [Indexed: 02/07/2023]
Abstract
Statin drugs are widely used worldwide and are generally considered safe and well tolerated. Only small proportion of patients receiving statins develop elevations of liver enzymes and an even smaller proportion will have clinically significant hepatitis induced by statins. We describe four patients with jaundice caused by drug-induced liver injury, where the most likely agent was a statin drug, over a period of approximately three year in Iceland. We calculate the risk of jaundice caused by statin drugs, from sale in the whole country of Iceland, to be one in 17,434 users a year. This is a higher risk than has previously been estimated and we challenge the current opinion that statins rarely cause clinically significant drug-induced liver injury and encourage alertness when managing patients with statins with regard to clinical signs of hepatitis before jaundice occurs.
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Affiliation(s)
- Ottar M Bergmann
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavik, Iceland
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Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012; 56:374-80. [PMID: 21889469 DOI: 10.1016/j.jhep.2011.07.023] [Citation(s) in RCA: 208] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 07/08/2011] [Accepted: 07/26/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Limited data exist on drug-induced liver injury (DILI) associated with statins. METHODS Reports on adverse reactions suspected to be due to statins received by the Swedish Adverse Drug Reactions Advisory Committe 1988-2010 were analyzed. Only cases with >5×upper limit of normal (ULN) in aminotransferases and/or alkaline phosphatase >2×ULN were included. RESULTS The most common types of ADRs suspected were DILI in 124/217 (57%) cases. A total of 73/124 (59%) cases had at least possible relationship, median age 64 years (57-73), 55% males, whereas 25/124 cases (20%) were excluded due to mild elevations of liver tests and 26 due to unlikely relationship and/or lack of data. A statin-related DILI episode was reported in 1.2/100,000 users. Atorvastatin was implicated in 30/73 (41%) cases, simvastatin in 28 (38%), fluvastatin (15%), and others. Two patients died of acute liver failure, one underwent liver transplantation and 25 (34%) had jaundice. Three patients were rechallenged with the same statin producing similar patterns of liver injury. The median duration of therapy was 90 days (30-120), 120 (39-248) for atorvastatin, and 75 (30-150) for simvastatin (NS). Cholestatic/mixed injury was more common with atorvastatin, 17/30 (56%) than with simvastatin, 7/28 (24%) (p=0.018). CONCLUSIONS Idiosyncratic liver injury associated with statins is rare but can be severe. After recovery, a similar pattern of liver injury can be reproduced on re-exposure. Most patients experience liver injury 3-4 months after start of therapy. Atorvastatin is mostly associated with cholestatic liver injury whereas hepatocellular injury is more common with simvastatin.
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Affiliation(s)
- Einar Björnsson
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, The National University Hospital, Reykjavik, Iceland.
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Marchesini G, Moscatiello S, Agostini F, Villanova N, Festi D. Treatment of non-alcoholic fatty liver disease with focus on emerging drugs. Expert Opin Emerg Drugs 2011; 16:121-36. [PMID: 21352073 DOI: 10.1517/14728214.2011.531700] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is becoming one of the most common causes of chronic liver disease worldwide. The economic and social cost of disease is very high and there is a need for effective treatments. AREAS COVERED The available and potential future treatments for NAFLD are reviewed. EXPERT OPINION Weight loss remains the cornerstone of treatment of hepatic steatosis, but difficult to pursue. A pragmatic approach relies on generic recommendations for weight loss and physical activity in the whole population and limiting interventions to subject at risk of disease progression, but the type of preferred treatment remains a matter of debate. The large number and mechanistic diversity of drugs that have so far been investigated bear testimony to the lack of a specific, effective agent. Insulin resistance remains the pivotal alteration responsible for liver disease and its progression and insulin sensitizers are regarded as the treatment of choice. Several ongoing studies are testing the effectiveness of new approaches on histological outcomes and new metabolic pathways are under scrutiny.
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Affiliation(s)
- Giulio Marchesini
- University of Bologna, Unit of Metabolic Diseases & Clinical Dietetics, 9, Via Massarenti, I-40138 Bologna, Italy.
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Heeba GH, Abd-Elghany MI. Effect of combined administration of ginger (Zingiber officinale Roscoe) and atorvastatin on the liver of rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2010; 17:1076-81. [PMID: 20576411 DOI: 10.1016/j.phymed.2010.04.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 03/07/2010] [Accepted: 04/27/2010] [Indexed: 05/29/2023]
Abstract
Ginger is known to possess hypolipidemic, antioxidant and hepatoprotective properties. Combination therapy often takes advantage of complementary effects of different agents. This study investigated the combined effect of ginger extract (GE) and atorvastatin on lipid profile and on atorvastatin-induced hepatic injury. Rats were randomized into: control; GE (400 mg/kg); atorvastatin (20 mg/kg) alone or with GE or vitamin E, and atorvastatin (80 mg/kg) alone or with GE or vitamin E. Administration of 80 mg/kg atorvastatin for 4 weeks had major hepatotoxic effect whereas the lower dose (20 mg/kg) seems to cause mild liver injury. Besides lowering serum total cholesterol and hepatic superoxide dismutase (SOD) and catalase (CAT), atorvastatin significantly increased serum aminotransferases, hepatic malondialdehyde (MDA) and nitric oxide (NO). Concurrent administration of GE and atorvastatin had the opposite effect. Histopathological study revealed that GE reduced liver lesions induced by atorvastatin. The results indicate that the ability of ginger to lower serum cholesterol and to decrease aminotransferases, MDA and NO is clinically important, because its chronic administration will neither lead to side-effects nor to hepatic changes as occurs with high atorvastatin doses. Therefore, combination regimens containing GE and low dose of statins could be advantageous in treating hypercholesterolemic patients which are susceptible to liver function abnormalities.
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Affiliation(s)
- Gehan H Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt.
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Abstract
Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI.
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Affiliation(s)
- Stefan Russmann
- Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland
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Garip S, Yapici E, Ozek NS, Severcan M, Severcan F. Evaluation and discrimination of simvastatin-induced structural alterations in proteins of different rat tissues by FTIR spectroscopy and neural network analysis. Analyst 2010; 135:3233-41. [DOI: 10.1039/c0an00540a] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Cadranel JF, Seddik M, Loric S, Jeanne S. Statines : quelle hépatotoxicité et quelle surveillance? Presse Med 2009; 38:717-25. [DOI: 10.1016/j.lpm.2008.05.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Accepted: 05/07/2008] [Indexed: 11/30/2022] Open
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Tuteja S, Pyrsopoulos NT, Wolowich WR, Khanmoradi K, Levi DM, Selvaggi G, Weisbaum G, Tzakis AG, Schiff ER. Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. Pharmacotherapy 2008; 28:1188-1193. [PMID: 18752389 DOI: 10.1592/phco.28.9.1188] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
Abstract Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatinezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatinezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.
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Affiliation(s)
- Sony Tuteja
- Division of Clinical and Administrative Pharmacy, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
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Abstract
The effort to reduce cardiovascular risk factors, including hyperlipidemia, has led to the increased use of lipid-lowering agents. Hyperlipidemic patients often have underlying fatty liver disease, however, and thus may have elevated and fluctuating liver biochemistries. Therefore, caution should be applied before attributing elevated liver tests to lipid-lowering agents. Data indicate that patients who have chronic liver disease and compensated cirrhosis should not be precluded from receiving statins to treat hyperlipidemia. Several recent studies and expert opinion currently fully endorse statin use in patients who have nonalcoholic fatty liver disease and other chronic liver disease if clinically indicated.
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Affiliation(s)
- Sidharth S Bhardwaj
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 1001 West 10th Street, WD OPW 2005, Indianapolis, IN 46202, USA
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Ito DT, Molina HM, Andriolo A, Borges DR. The combination of atorvastatin and ethanol is not more hepatotoxic to rats than the administration of each drug alone. Braz J Med Biol Res 2007; 40:343-8. [PMID: 17334531 DOI: 10.1590/s0100-879x2007000300009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Accepted: 01/05/2007] [Indexed: 11/22/2022] Open
Abstract
Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group) consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v) ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase) from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption) was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.
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Affiliation(s)
- D T Ito
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, Av. Dr. Enéas C. Aguiar, 05403-000 São Paulo, SP, Brazil
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Conforti A, Magro L, Moretti U, Scotto S, Motola D, Salvo F, Ros B, Leone R. Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy. Drug Saf 2007; 29:1163-72. [PMID: 17147462 DOI: 10.2165/00002018-200629120-00007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population. OBJECTIVE In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature. METHODS The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'. RESULTS At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage. CONCLUSION In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.
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Affiliation(s)
- Anita Conforti
- Clinical Pharmacology Unit, Reference Centre for Education and Communication, WHO Programme for International Drug Monitoring, University of Verona, Verona, Italy
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Clarke AT, Mills PR. Atorvastatin associated liver disease. Dig Liver Dis 2006; 38:772-7. [PMID: 16777499 DOI: 10.1016/j.dld.2006.04.013] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2006] [Revised: 04/13/2006] [Accepted: 04/18/2006] [Indexed: 12/11/2022]
Abstract
Atorvastatin, a HMG-CoA reductase inhibitor, is widely used in the treatment of dyslipidaemia. A transient rise in serum transaminases occurs in up to 3% of patients using atorvastatin but this is usually self-limiting and inconsequential. Recent literature has indicated some potential for more serious but rare idiosyncratic reactions related to this drug. Seven patients with significant liver dysfunction from one centre during 2002-2005 are reported, with one death, that raises some concern over the safety of atorvastatin. A total of seven other patients are reported in the literature. The 14 patients were usually over 60 years, had a female:male ratio of 2:1 and showed a mixed cholestatic/hepatocellular reaction. The mean interval to onset of reaction was approximately 9 weeks and the liver often took several months to recover. Three deaths occurred. Adverse drug reaction reports from the UK Committee on Safety of Medicines reveal that four deaths due to hepatobiliary disease (0.5 deaths per annum) have been reported in association with atorvastatin treatment over 8 years. Simvastatin has had no hepatobiliary-related fatalities reported over 15 years. While acute hepatotoxicity with atorvastatin remains uncommon, any persistent abnormality in liver function should be treated with caution.
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Affiliation(s)
- A T Clarke
- Gastroenterology Unit, Gartnavel General Hospital, Glasgow, UK.
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Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006; 23:1643-7. [PMID: 16696815 DOI: 10.1111/j.1365-2036.2006.02926.x] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies available. Atorvastatin is a new 3-hydroxy-3-metylglutaryl coenzyme A reductase inhibitor that reduces lipid serum levels. AIM To evaluate the effectiveness and safety of atorvastatin in dyslipemid, non-alcoholic fatty liver patients. PATIENTS AND METHODS We prospectively enrolled 25 patients with NAFLD; 22 of them completed the study. Body mass index, serum lipids, liver function tests and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treatment. Normalization of transaminases and/or improvement in liver density were treatment end points. Patients received atorvastatin (10-80 mg/daily) according to basal serum choleresterol levels; additionally, they were given standard weight-loss counselling and encouraged to follow a low fat diet. RESULTS All 22 patients (14 men, mean age 47 +/- 10 years) had high cholesterol levels at baseline and 11 (44%) also presented high trygliceride levels. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months when 20% of patients presented with normal transaminase levels, while the other patients showed a 10% reduction in basal levels. Mean cholesterol levels were 268.5 +/- 44.2 and 186.8 +/- 14.4 mg/dL before and after treatment, respectively (P < 0.05). The mean body mass index was 27.4 +/- 3.1 at baseline and 26.3 +/- 2.8 kg/cm2 at the end of treatment (P > 0.05). No side effects were reported. CONCLUSIONS Serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment. Therapy with atorvastatin in NAFLD patients with hyperlipidemia was found to be both effective and safe.
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Affiliation(s)
- E Gómez-Domínguez
- Gastroenterology and Hepatology Service, Hospital Universitario la Princesa and Instituto de Salud Carlos III, Madrid, Spain
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Abstract
Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.
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Affiliation(s)
- Terry A Jacobson
- Office of Health Promotion and Disease Prevention, Emory University School of Medicine, Atlanta, GA 30303, USA.
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de Castro ML, Hermo JA, Baz A, de Luaces C, Pérez R, Clofent J. Hepatitis colestásica aguda tras la reintroducción de atorvastatina. GASTROENTEROLOGIA Y HEPATOLOGIA 2006; 29:21-4. [PMID: 16393626 DOI: 10.1157/13083248] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Consumption of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, known as statins, has been associated with elevated transaminase levels but rarely with acute hepatitis. Recently, several cases of acute hepatitis secondary to atorvastatin therapy have been published. We report the case of a 72-year-old man who developed acute cholestatic hepatitis after reinitiating treatment with atorvastatin at a higher dose than that previously prescribed. After treatment discontinuation, the patient made a full recovery, with normalization of clinical and laboratory findings.
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Affiliation(s)
- M L de Castro
- Servicio de Aparato Digestivo, Hospital Meixoeiro-CHUVI Vigo, Pontevedra, Spain.
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Affiliation(s)
- Naga Chalasani
- Indiana University School of Medicine, Indianopolis, IN 46202, USA.
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